A Randomized, Open-label, Multicenter, Phase 3 Trial Evaluating Brelovitug vs Delayed Treatment for the Treatment of Chronic Hepatitis Delta Infection (AZURE-4)

Trial ID: 2025-522105-38-00
Protocol: BJT-778-304
Sponsor: Mirum Pharmaceuticals Inc.

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Diseases & Conditions

Hepatitis D

Objectives

The primary objective is to evaluate the efficacy of brelovitug at Week 24 compared with delayed treatment on chronic hepatitis delta at Week 12. This objective aims to determine whether immediate initiation of brelovitug therapy demonstrates superior therapeutic benefit compared to a 12-week treatment delay in patients with chronic hepatitis delta infection.

The secondary objectives include:

• To evaluate the safety and tolerability of chronic treatment with brelovitug and in comparison to 12-week delayed treatment.

• To characterize the efficacy of chronic treatment with brelovitug and in comparison to Week 12 delayed treatment on HDV.

• To evaluate the HDV clearance rates after 96 weeks of treatment in subjects who do not rollover to the extended treatment protocol.

• To evaluate the effect of chronic treatment with brelovitug on HDV disease progression, including assessment of HDV-related liver disease progression.

Participants

The clinical trial enrolled a total of **63 participants** diagnosed with **chronic hepatitis delta infection**. The study population included both **male and female subjects** aged **18 years and older**. Participants were selected based on confirmation of chronic HDV infection, defined as positive anti-HDV antibody test or **HDV RNA** for at least 6 months prior to enrollment, or HDV RNA positivity with evidence of **fibrosis** (liver stiffness ≥7 kPa). Eligible participants demonstrated HDV RNA levels exceeding 500 IU/mL and **alanine aminotransferase (ALT)** levels above the upper limit of normal at screening. All participants were required to be taking or willing to take **tenofovir disoproxil fumarate (TDF)**, **tenofovir alafenamide fumarate (TAF)**, or **entecavir (ETV)** at baseline and to maintain stable treatment throughout the study duration. In countries where HDV treatment is approved and available, participants were documented as unwilling or unable to receive such treatment. The trial population represented individuals with active chronic hepatitis delta requiring therapeutic intervention while maintaining concurrent antiviral therapy for hepatitis B virus co-infection.

Plans and Procedures

This is a randomized, open-label, multicenter, Phase 3 clinical trial evaluating the efficacy and safety of brelovitug (BJT-778) compared with delayed treatment in participants with chronic hepatitis delta infection. The investigational medicinal product BJT-778 is a protein-based active substance administered as a solution for injection via subcutaneous injection. BJT-778 has been designated as an orphan drug for this rare disease condition. The maximum daily dose is 900 mg, with a maximum total dose of 28,800 mg over a treatment period of up to 96 weeks. Participants are required to be taking or willing to take tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, or entecavir at baseline and must remain on stable treatment throughout the study duration.

The primary objective is to evaluate the efficacy of brelovitug at Week 24 compared with delayed treatment at Week 12. The primary endpoint is the proportion of participants achieving a composite endpoint consisting of virologic response and ALT normalization at Week 24 in the brelovitug treatment arms compared to Week 12 in the delayed-treatment arm. Virologic response is defined as HDV RNA reduction of at least 2 log10 IU/mL from baseline or undetectable HDV RNA. ALT normalization is defined as a decrease in alanine aminotransferase from baseline to at or below the upper limit of normal. Secondary endpoints include safety assessments evaluating the incidence and severity of treatment-emergent adverse events and the proportion of participants who permanently discontinue treatment due to an adverse event. Additional secondary endpoints assess virologic response, changes in liver stiffness as determined by transient elastography, changes in AST-to-platelet ratio index, changes in Child-Turcotte-Pugh score in cirrhotic participants, changes in Model for End-Stage Liver Disease score in cirrhotic participants, and the proportion of participants with clinical disease progression at Weeks 24, 48, and 96 of brelovitug treatment.

Eligible participants include males and females aged 18 years or older at screening who provide written informed consent. Participants must have confirmed chronic HDV infection, defined as positive anti-HDV antibody test or HDV RNA for at least 6 months prior to Day 1, or HDV RNA positivity along with evidence of fibrosis (liver stiffness of at least 7 kPa) if prior documentation is unavailable. At screening, participants must have HDV RNA greater than 500 IU/mL and ALT above the upper limit of normal. In countries where HDV treatment is approved and available, participants must be documented as unwilling or unable to receive treatment. The estimated recruitment start date is January 30, 2026, with an estimated study completion date of January 24, 2028.

The overall trial duration extends up to 96 weeks of treatment for participants receiving brelovitug. Participants randomized to the delayed-treatment arm will have assessments at Week 12 before initiating brelovitug treatment. Study visits include a screening visit to assess eligibility criteria, baseline assessments on Day 1, and follow-up visits at designated time points including Weeks 12, 24, 48, and 96 to evaluate efficacy and safety endpoints. An Independent Data Monitoring Committee will assess clinical disease progression throughout the study. Participants may be subject to early termination from the study due to adverse events requiring permanent discontinuation of treatment, withdrawal of consent, or other conditions as determined by the investigator or sponsor. The length of participant involvement varies depending on treatment allocation, with those in the brelovitug arms participating for up to 96 weeks and those in the delayed-treatment arm initially assessed at Week 12 before crossing over to active treatment.

Treatment

The experimental treatment consists of **BJT-778** (brelovitug), a protein-based investigational medicinal product designated as an **orphan drug** (EMA/OD/0000167926). The active substance is BJT-778, classified as a protein of other origin. The product is manufactured by Bluejay Therapeutics, Inc.

BJT-778 is formulated as a **solution for injection** and is administered via **subcutaneous injection**. The maximum daily dose is **900 mg**, with a maximum total dose of **28,800 mg** over a treatment period of up to **96 weeks**. The dosing regimen and administration schedule are designed to evaluate the efficacy of brelovitug in the treatment of **chronic hepatitis delta infection**.

The trial employs a **randomized, open-label, multicenter design** comparing brelovitug treatment with **delayed treatment** as the control arm. Participants in the delayed treatment group serve as comparators to assess the efficacy of brelovitug at Week 24 compared with delayed treatment on chronic hepatitis delta at Week 12. The study protocol includes monitoring of participant compliance with the prescribed dosing schedule throughout the treatment period.

Efficacy

Efficacy will be assessed using a composite primary endpoint evaluated at Week 24 in the brelovitug treatment arms compared to Week 12 in the delayed-treatment arm. The composite endpoint consists of two parameters: virologic response and ALT normalization. Virologic response is defined as HDV RNA reduction of ≥2 log10 IU/mL from baseline or undetectable HDV RNA. ALT normalization is defined as a decrease in alanine aminotransferase from baseline to ≤ upper limit of normal.

Secondary efficacy endpoints will be assessed at multiple timepoints including Weeks 24, 48, and 96 of treatment. These include the proportion of participants achieving virologic response defined as ≥2 log10 IU/mL decline from baseline or undetectable HDV RNA, and the proportion achieving undetectable HDV RNA. Changes from baseline in liver stiffness as determined by transient elastography will be measured at Weeks 24, 48, and 96. Changes from baseline in AST-to-platelet ratio index will be assessed at the same timepoints. In cirrhotic participants, changes from baseline in Child-Turcotte-Pugh score and Model for End-Stage Liver Disease score will be evaluated at Weeks 24, 48, and 96. The proportion of participants with clinical disease progression from baseline in HDV-associated liver disease will be determined by the Independent Data Monitoring Committee at Weeks 24, 48, and 96 of brelovitug treatment.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Willing and able to provide written informed consent.
Male or female, ≥18 years of age at Screening.
Confirmation of chronic HDV infection, defined as positive for anti-HDV antibody test or HDV RNA for at least 6 months prior to Day 1. If prior documentation is not available, then HDV RNA positivity along with evidence of fibrosis (liver stiffness of ≥7 kPa) is acceptable.
HDV RNA >500 IU/mL at Screening.
ALT >ULN at Screening.
Taking or willing to take tenofovir disoproxil fumarate (TDF), tenofovir alafenamide fumarate (TAF), or entecavir (ETV) at baseline, and willing to remain on stable treatment for the duration of the study.
In countries where HDV treatment is approved and available, participants must be documented as unwilling or unable to receive treatment.

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Exclusion Criteria

Pregnant or nursing females.
9.Treatment with another investigational drug, a biological agent, or device within 4 weeks or 5 half-lives, whichever is longer, of Baseline.
Use of any interferon within 12 weeks of Screening.
Use of any prohibited concomitant medications as described in Study Protocol.
Regular alcohol misuse, defined as weekly intake of ≥14 alcoholic drinks per week (average of ≥2 alcoholic drinks per day) within 12 months of Screening.
Clinically relevant drug abuse (not including cannabis) within 12 months of Screening.
Unwillingness to comply with study procedures as specified by this protocol, or unwillingness to cooperate fully with the Investigator.
Have any other conditions (medical, social, psychiatric, or other), which in the opinion of the Investigator would make the participant unsuitable for inclusion or could interfere with the participant participating in or completing the study.
Male or female participants of childbearing potential unwilling to comply with contraception requirements during the study.
Current, prior history, or is under evaluation for any of the following: a) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy, b) Clinical hepatic decompensation (i.e., ascites, encephalopathy variceal hemorrhage). Incidental small ascites on imaging without other clinical symptoms/signs of acute decompensation would not exclude the participants, c) Hepatocellular carcinoma; suspected HCC on ultrasound at Screening, d) Vasculitis, e) Extrahepatic disorders possibly related to HBV immune complexes (e.g., glomerulonephritis, polyarteritis nodosa), f) Solid organ or bone marrow transplantation, g) Significant pulmonary disease (e.g., O2-dependent or forced expiratory volume 1 second (FEV1) ≤50% predicted value), h) Significant cardiac disease (e.g., history of myocardial infarctions within 6 months, any history of ventricular tachycardia, congestive heart failure, dilated cardiomyopathy with left ventricular ejection fraction <40%), i)Malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to Screening).
CTP >6 (B or C)
Presence of other liver disease(s) (non-HBV/HDV), such as metabolic dysfunction-associated steatohepatitis (MASH), alcohol associated hepatitis, cholestatic liver disease, other viral (e.g., HCV or HAV) or non-viral hepatitis that has the potential to impact interpretation of data. Exceptions to this criterion include fatty liver without any signs of steatohepatitis or past HCV infection that was successfully treated (HCV RNA negative) ≥6 months prior to Screening.
Uncontrolled human immunodeficiency virus (HIV) infection defined as having quantifiable HIV RNA levels in the blood at Screening.
History of hypersensitivity to any of the components in the brelovitug formulation.
Screening laboratory results as follows, or any other clinically significant abnormalities in Screening laboratory values that would render a participant unsuitable for inclusion: a) Platelet count <50,000/mm3 b) Hemoglobin <10.0 g/dL c) Creatinine clearance by Crockcroft-Gault (CrCl) <30 mL/min d) Alpha fetoprotein (AFP) >100 ng/mL